N-methyl-D-aspartate (NMDA) receptors are ligand-gated cation-channels widely expressed in the central nervous system. NMDA receptors are involved in developmental and plastic changes of neurons. Overactivation of NMDA receptors by glutamate, their natural ligand, can lead to calcium overload of cells. This triggers a cascade of intracellular events that alters the cell function and ultimately may lead to death of neurones. Antagonists of the NMDA receptors may be used for treating many disorders that are accompanied with excess release of glutamate or overactivation of NMDA receptor for any reason [Curr Opin Investig Drugs. 2003 4: 826-32].
The NMDA receptors are heteromeric assemblies built up from at least one NR1 subunit together with one or more of the four NR2 subunits (NR2A-D). Both spatial distributions in the CNS and the pharmacological sensitivity of NMDA receptors built up from various NR2 subunits are different. Particularly interesting of these is the NR2B subunit due to its restricted distribution (highest densities in the forebrain and substantia gelatinosa of the spinal cord) [Neuropharmacology, 38, 611-623 (1999)]. Compounds selective for this subtype are available and have been proved to be effective in animal models of stroke [Stroke, 28, 2244-2251 (1997)], traumatic brain injury [Brain Res., 792, 291-298 (1998)], Parkinson's disease [Exp. Neurol., 163, 239-243 (2000)], neuropathic and inflammatory pain [Neuropharmacology, 38, 611-623 (1999)].
Moreover, NR2B subtype selective antagonists of NMDA receptors may provide therapeutic advantage over non-selective antagonists of NMDA receptors. The channel blocker type non-selective NMDA antagonists phencyclidine and ketamine induce psychotomimetic effects, hallucinations, dysphoria, catatonia and amnesia in man. These serious adverse effects hinder their clinical use as potential medication. Compounds belonging to this class cause behavioural abnormalities in animals, too, e.g. stimulate motor activity, induce, amnesia and impair motor-coordination. The severity of these effects in animals is considered to be predictive for the intensity of clinical side effects. NR2B subtype selective antagonists are expected to lack most of these side effects. In animal behavioural studies some NR2B selective compounds [Ro 63-1908 in J. Pharmacol. Exp. Ther., 302 (2002) 940-948 and Ro 25-6981 in Behav. Pharmacol., 14 (2003) 477-487] were reported to increase locomotor activity while no such effect was observed with CP-101,606, another NR2B selective antagonist, and Ro 256981 by an other group [Neuropharmacology, 38, 611-623 (1999)]. Lack of locomotor stimulating effect of CP-101,606 up to 56 mg/kg s.c. and 100 mg/kg i.p. was confirmed by others [Soc. Neurosc. Abstr. 21, 439.9. 1995.]. Thus, to our best knowledge, CP-101,606 is the only NR2B selective antagonist consistently reported to lack locomotor stimulating effect. Since CP-101,606 appears to have poor oral efficacy and according to published information was investigated only by intravenous route of administration in humans, moreover it has polymorph CYP2D6 mediated metabolism [Drug Metabolism and Disposition 31: 76-87], there remains to be a great need for new NR2B antagonists with low side effect liability (high therapeutic index) good oral efficacy (bioavailability) and good developability for therapeutic purposes, especially for oral treatment.
Saturated analogues of the compounds of the present invention are described in patent No. WO 2003010159 as NR2B subtype selective NMDA antagonists. However, other close structure analogues of the 4-benzylidene-piperidine derivatives of formula (I) are unknown in the literature.